KONDO Tsunenori
   Department   School of Medicine(Tokyo Women's Medical University Adachi Medical Center), School of Medicine
   Position   Professor
Article types Original article
Language English
Peer review Non peer reviewed
Title Pharmacokinetic Modeling and Monte Carlo Simulation to Predict Interindividual Variability in Human Exposure to Oseltamivir and Its Active Metabolite, Ro 64-0802.
Journal Formal name：The AAPS journal
Abbreviation：AAPS J
ISSN code：15507416/15507416
Domestic / ForeginForegin
Volume, Issue, Page 19(1),pp.286-297
Author and coauthor Ito Mototsugu, Kusuhara Hiroyuki, Ose Atsushi, Kondo Tsunenori, Tanabe Kazunari, Nakayama Hideki, Horita Shigeru, Fujita Takuya, Sugiyama Yuichi
Publication date 2017/01
Summary Oseltamivir (Tamiflu®) is a prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. There is a possible relationship between oseltamivir treatment and neuropsychiatric adverse events; although this has not been established, close monitoring is recommended on the prescription label. The objective of this study was to predict interindividual variability of human exposure to oseltamivir and its active metabolite Ro 64-0802. By leveraging mathematical models and computations, physiological parameters in virtual subjects were generated with population means and coefficient of variations collected from the literature or produced experimentally. Postulated functional changes caused by genetic mutations in four key molecules, carboxylesterase 1A1, P-glycoprotein, organic anion transporter 3, and multidrug resistance-associated protein 4, were also taken into account. One hundred thousand virtual subjects were generated per simulation, which was iterated 20 times with different random number generator seeds. Even in the most exaggerated case, the systemic areas under the concentration-time curve (AUCs) of oseltamivir and Ro 64-0802 were increased by at most threefold compared with the population mean. By contrast, the brain AUCs of oseltamivir and Ro 64-0802 were increased up to about sevenfold and 40-fold, respectively, compared with the population means. This unexpectedly high exposure to oseltamivir or Ro 64-0802, which occurs extremely rarely, might trigger adverse central nervous system effects in the clinical setting.
DOI 10.1208/s12248-016-9992-0
PMID 27800573